ml-10302 and Cognition-Disorders

Alzheimer's disease (AD) is a neurodegenerative disease which has a higher prevalence and incidence in older people. The need for improved AD therapies is unmet. The 5-hydroxytryptamine4 receptor (5-HT4R) partial agonists may be of benefit for both the symptomatic and disease-modifying treatment of cognitive disorders associated with AD. Herein, we report the design, synthesis and SAR of imidazo[1,5-a] pyridine derivatives as 5-HT4R partial agonists. The focused SAR, optimization of ADME properties resulted the discovery of compound 5a as potent, selective, brain penetrant 5-HT4 partial agonist as a lead compound with good ADME properties and efficacy in both symptomatic and disease modifying animal models of cognition.

Topics: Alzheimer Disease; Animals; Cognition Disorders; Dogs; Dose-Response Relationship, Drug; Drug Design; Drug Partial Agonism; Humans; Molecular Structure; Pyridines; Rats; Receptors, Serotonin, 5-HT4; Structure-Activity Relationship